Family, twin and adoption studies have consistently shown that genetic factors are of major etiologic importance in schizophrenia. Since early in this century, it has been suggested that there are single genes of "major effect" for schizophrenia. Recent advances in molecular biology and in statistical approaches to linkage analysis now provide us, for the first time, with the techniques to rigorously evaluate this claim. This is a proposal to conduct linkage analyses on a large number of multiplex pedigrees for schizophrenia that are currently being ascertained and sampled in Ireland (MH-41953). This study will utilize the abundant, highly polymorphic DNA markers that have recently become available to span virtually the entire human genome as well as potential candidate genes. This proposal seeks to capitalize on the unique resource of high density Irish schizophrenic pedigrees that include: i) a relatively homogeneous ethnic composition of the population, which should reduce the problems of genetic heterogeneity; ii) enhanced ability to determine optimal diagnostic criteria, and estimates of gene frequency and penetrance necessary for linkage analyses by utilizing data obtained from a large sample epidemiologically based family study currently nearing completion in the West of Ireland and iii) the close genetic relationship between Ireland and both Iceland and England, the countries in which pedigrees have been ascertained that demonstrate significant linkage to markers on chromosome 5. Genetic markers throughout the genome will be typed for the high density schizophrenic families, first concentrating in areas that previous studies suggest might be of potential relevance to schizophrenia. Several distinct statistical methodologies of segregation and linkage analysis will be applied to the data in order to fully utilize their potential. Any strong positive findings will be pursued by cloning additional markers from that part of the genome where a major locus for schizophrenia might lie, in order to map the locus more precisely.